tbuckley/cabot-search huggingface dataset:
B-cell Receptor Signaling Induced Metabolic Alterations in Chronic Lymphocytic Leukemia Can Be Partially Bypassed by TP53 Abnormalities
Authors: Katarina Kluckova, Andrew J. Clear, Annalisa D’Avola, Laura Z. Rassenti, Thomas J. Kipps, John G. Gribben, John C. Riches
Journal: HemaSphere (2022)

It has been unclear what role metabolism is playing in the pathophysiology of chronic lymphocytic leukemia (CLL). One reason is that the study of CLL metabolism is challenging due to the resting nature of circulating CLL cells. Also, it is not clear if any of the genomic aberrations observed in this disease have any impact on metabolism. Here, we demonstrate that CLL cells in proliferation centers exhibit upregulation of several molecules involved in glycolysis and mitochondrial metabolism. Comparison of CXCR4/CD5 intraclonal cell subpopulations showed that these changes are paralleled by increases in the metabolic activity of the CXCR4lowCD5high fraction that have recently egressed from the lymph nodes. Notably, anti-IgM stimulation of CLL cells recapitulates many of these metabolic alterations, including increased glucose uptake, increased lactate production, induction of glycolytic enzymes, and increased respiratory reserve. Treatment of CLL cells with inhibitors of B-cell receptor (BCR) signaling blocked these anti-IgM-induced changes in vitro, which was mirrored by decreases in hexokinase 2 expression in CLL cells from ibrutinib-treated patients in vivo. Interestingly, several samples from patients with 17p-deletion manifested increased spontaneous aerobic glycolysis in the unstimulated state suggestive of a BCR-independent metabolic phenotype. We conclude that the proliferative fraction of CLL cells found in lymphoid tissues or the peripheral blood of CLL patients exhibit increased metabolic activity when compared with the bulk CLL-cell population. Although this is due to microenvironmental stimulatory signals such as BCR-engagement in most cases, increases in resting metabolic activity can be observed in cases with 17p-deletion.
Abstract A011: Deciphering clonal evolution under chemotherapy in high-risk neuroblastoma using patient derived models
Authors: Natalie Andersson, Adriana Mañas Nuñez, Kristina Aaltonen, Karin Hansson, Alexandra Seger, Katarzyna Radke, Javanshir Esfandyari, Daniel Bexell, David Gisselsson
Journal: Cancer Research (2022)

Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Proffered Abstracts section (PR001) of the Conference Proceedings. Citation Format: Natalie Andersson, Adriana Mañas Nuñez, Kristina Aaltonen, Karin Hansson, Alexandra Seger, Katarzyna Radke, Javanshir Esfandyari, Daniel Bexell, David Gisselsson. Deciphering clonal evolution under chemotherapy in high-risk neuroblastoma using patient derived models [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A011.
Epithelial–mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities
Authors: Zhao Huang, Zhe Zhang, Chengwei Zhou, Lin Liu, Canhua Huang
Journal: MedComm (2022)

Abstract Epithelial–mesenchymal transition (EMT) is a program wherein epithelial cells lose their junctions and polarity while acquiring mesenchymal properties and invasive ability. Originally defined as an embryogenesis event, EMT has been recognized as a crucial process in tumor progression. During EMT, cell–cell junctions and cell–matrix attachments are disrupted, and the cytoskeleton is remodeled to enhance mobility of cells. This transition of phenotype is largely driven by a group of key transcription factors, typically Snail, Twist, and ZEB, through epigenetic repression of epithelial markers, transcriptional activation of matrix metalloproteinases, and reorganization of cytoskeleton. Mechanistically, EMT is orchestrated by multiple pathways, especially those involved in embryogenesis such as TGFβ, Wnt, Hedgehog, and Hippo, suggesting EMT as an intrinsic link between embryonic development and cancer progression. In addition, redox signaling has also emerged as critical EMT modulator. EMT confers cancer cells with increased metastatic potential and drug resistant capacity, which accounts for tumor recurrence in most clinic cases. Thus, targeting EMT can be a therapeutic option providing a chance of cure for cancer patients. Here, we introduce a brief history of EMT and summarize recent advances in understanding EMT mechanisms, as well as highlighting the therapeutic opportunities by targeting EMT in cancer treatment.
Effect of Robot-Assisted Radical Cystectomy With Intracorporeal Urinary Diversion vs Open Radical Cystectomy on 90-Day Morbidity and Mortality Among Patients With Bladder Cancer
Authors: James W. F. Catto, Pramit Khetrapal, Federico Ricciardi, Gareth Ambler, Norman R. Williams, Tarek Al-Hammouri, Muhammad Shamim Khan, Ramesh Thurairaja, Rajesh Nair, Andrew Feber, Simon Dixon, Senthil Nathan, Tim Briggs, Ashwin Sridhar, Imran Ahmad, Jaimin Bhatt, Philip Charlesworth, Christopher Blick, Marcus G. Cumberbatch, Syed A. Hussain, Sanjeev Kotwal, Anthony Koupparis, John McGrath, Aidan P. Noon, Edward Rowe, Nikhil Vasdev, Vishwanath Hanchanale, Daryl Hagan, Chris Brew-Graves, John D. Kelly, E Ruth Groves, Louise Goodwin, Jayne Willson, Phillip Ravencroft, Stephen Kennish, Derek J Rosario, Carol Torrington, Rajesh Nair, Ramesh Thurairaja, Sue Amery, Kathryn Chatterton, Samantha Broadhead, David Hendry, Abdullah Zreik, Sunjay Jain, Steve Prescott, Hannah Roberts, Angela Morgan, Chris Main, Elspeth Bedford, Lorraine Wiseman, Bernice Mpofu, Claire Daisey, Michelle Donachie, Jon Aning, Lyndsey Johnson, Carol Brain, Constance Shiridzinomwa, Martin Ebon, Alexander Hampson, Roisin Schimmel, Scott Horsley, Sayyida Nembhard, Clare Collins, Jemma Gilmore, Faith Wilson, Louise Peacock, Sheena Lim, Rhosyll Gabriel, Rachael Sarpong, Melanie Tan
Journal: JAMA (2022)

Robot-assisted radical cystectomy is being performed with increasing frequency, but it is unclear whether total intracorporeal surgery improves recovery compared with open radical cystectomy for bladder cancer.
Population Genetics and Signatures of Selection in Early Neolithic European Farmers
Authors: Ainash Childebayeva, Adam Benjamin Rohrlach, Rodrigo Barquera, Maïté Rivollat, Franziska Aron, András Szolek, Oliver Kohlbacher, Nicole Nicklisch, Kurt W. Alt, Detlef Gronenborn, Harald Meller, Susanne Friederich, Kay Prüfer, Marie-France Deguilloux, Johannes Krause, Wolfgang Haak
Journal: Molecular Biology and Evolution (2022)

Abstract Human expansion in the course of the Neolithic transition in western Eurasia has been one of the major topics in ancient DNA research in the last 10 years. Multiple studies have shown that the spread of agriculture and animal husbandry from the Near East across Europe was accompanied by large-scale human expansions. Moreover, changes in subsistence and migration associated with the Neolithic transition have been hypothesized to involve genetic adaptation. Here, we present high quality genome-wide data from the Linear Pottery Culture site Derenburg-Meerenstieg II (DER) (N = 32 individuals) in Central Germany. Population genetic analyses show that the DER individuals carried predominantly Anatolian Neolithic-like ancestry and a very limited degree of local hunter-gatherer admixture, similar to other early European farmers. Increasing the Linear Pottery culture cohort size to ∼100 individuals allowed us to perform various frequency- and haplotype-based analyses to investigate signatures of selection associated with changes following the adoption of the Neolithic lifestyle. In addition, we developed a new method called Admixture-informed Maximum-likelihood Estimation for Selection Scans that allowed us test for selection signatures in an admixture-aware fashion. Focusing on the intersection of results from these selection scans, we identified various loci associated with immune function (JAK1, HLA-DQB1) and metabolism (LMF1, LEPR, SORBS1), as well as skin color (SLC24A5, CD82) and folate synthesis (MTHFR, NBPF3). Our findings shed light on the evolutionary pressures, such as infectious disease and changing diet, that were faced by the early farmers of Western Eurasia.
Neutralizing Antibodies Against the SARS-CoV-2 Omicron Variant (BA.1) 1 to 18 Weeks After the Second and Third Doses of the BNT162b2 mRNA Vaccine
Authors: Ria Lassaunière, Charlotta Polacek, Anders Frische, Lasse Boding, Susanne Gjørup Sækmose, Morten Rasmussen, Anders Fomsgaard
Journal: JAMA Network Open (2022)

the observed decrease in population neutralizing antibody titers corresponds to the decrease in vaccine efficacy against polymerase chain reaction-confirmed Omicron infection in Denmark and symptomatic Omicron infection in the United Kingdom. 3,4Taken together, vaccine-induced protective antibody responses following a second and third dose of BNT162b2 are transient and additional booster doses may be necessary, particularly in older people; however, conserved T-cell immunity and nonneutralizing antibodies may still provide protection against hospitalization and death.
Re: Jiatong Zhou, Jie Ding, Jun Qi. Comparison of Typical Prostate Adenocarcinoma and Rare Histological Variant Prostate Cancer Showed Different Characteristics and Prognosis: A Surveillance, Epidemiology, and End Results Database Analysis. Eur Urol. 2022;82:152–5
Authors: Yuxuan Song, Yiqing Du, Tao Xu
Journal: European Urology (2022)
Radial incision and cutting under gel immersion as a useful method for refractory anastomotic stricture
Authors: Keisaku Yamada, Masahiro Tajika, Tsutomu Tanaka, Sachiyo Oonishi, Tomoyasu Kamiya, Yasumasa Niwa
Journal: Endoscopy (2022)

The radial incision and cutting method, in which the stricture is incised and the scar tissue excised, has shown promising results in the treatment of refractory anastomotic strictures [1] [2]. It is useful for refractory strictures that are not adequately dilated after repeated endoscopic balloon dilation.
Quantification and targeting of elusive neurotoxic amyloid oligomers
Authors: Nemil Bhatt, Rakez Kayed
Journal: Cell Reports Medicine (2022)

A study by Kass et al.1 aims to understand the size distribution of amyloid β oligomers in postmortem brain tissues from individuals with Alzheimer's disease (AD) and AD mouse models. Moreover, they show a dose-dependent oligomer elimination by the RD2 compound.
Abstract IA023: Selection for a glycolytic phenotype
Authors: Mehdi Damaghi
Journal: Cancer Research (2022)

Abstract In early breast carcinogenesis, neoplastic cells grow in multiple layers towards the lumens of ducts, which subjects the periluminal cells to harsh conditions of low oxygen, low pH, and nutrient deprivation. Adaptation to these harsh conditions is a pre-requisite for survival of incipient tumor cells and also responsible for selecting cells with a more aggressive phenotype. Based on the first principle of Darwinian evolution, common phenotypes of cancer cells must have conferred a selective advantage at some point during their evolutionary trajectory. Adaptations are initially acute and reversible, but eventually Darwinian selection results in cells with hardwired phenotypes. A prominent example of this is aerobic glycolysis, or the Warburg Effect (WE), wherein cells are hard-wired to ferment glucose, even in the presence of oxygen. WE provides and evolutionary advantage which leads to higher fitness of the cancer cells, who have acquired mechanisms of adaptation, such as autophagy and lysosome redistribution. Notably, a WE is highly correlated with a cancer’s metastatic potential and poor outcome. Hence, a major question in carcinogenesis is: “What are the mechanisms by which a harsh microenvironment eventually selects for hard-wired (heritable) phenotypes, such as a WE?”. Rather than simply selection of pre-existing phenotypes, we contend that the microenvironment actively induces phenotypic diversity through a systematic set of epigenetic and genetic alterations. Citation Format: Mehdi Damaghi. Selection for a glycolytic phenotype [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA023.
Benefits of aerobic exercise in myotonic dystrophy type 1
Authors: Samuel J. Mackenzie, Johanna Hamel, Charles A. Thornton
Journal: Journal of Clinical Investigation (2022)

Myotonic dystrophy type 1 (DM1) is a multisystem trinucleotide repeat expansion disorder characterized by the misregulated alternative splicing of critical mRNAs. Previous work in a transgenic mouse model indicated that aerobic exercise effectively improves splicing regulation and function in skeletal muscle. In this issue of the JCI, Mikhail et al. describe the safety and benefits of applying this approach in individuals affected by DM1. A 12-week aerobic exercise program improved aerobic capacity and mobility, but not by the mechanism observed in transgenic mice. Here, we consider the possible reasons for this disparity and review other salient findings of the study in the context of evolving DM1 research.
Arginase-1 Is Required for Macrophage-Mediated Renal Tubule Regeneration
Authors: Naomi S. Shin, Arnaud Marlier, Leyuan Xu, Natnael Doilicho, Daniel Linberg, Jiankan Guo, Lloyd G. Cantley
Journal: Journal of the American Society of Nephrology (2022)

Significance Statement Proinflammatory macrophages that infiltrate the kidney after ischemia-reperfusion injury later transition to a proreparative state characterized by expression of multiple proteins including arginase-1 ( Arg1 ). By comparing the kidney repair response after ischemia-reperfusion injury in mice that lack macrophage Arg1 expression with littermate controls, we show that macrophage Arg1 plays a critical role in renal recovery in part by promoting renal epithelial cell proliferative repair. Thus, therapeutic interventions that enhance Arg1 expression may improve renal recovery after kidney injury. Background After kidney injury, macrophages transition from initial proinflammatory activation to a proreparative phenotype characterized by expression of arginase-1 ( Arg1 ), mannose receptor 1 ( Mrc1 ), and macrophage scavenger receptor 1 ( Msr1 ). The mechanism by which these alternatively activated macrophages promote repair is unknown. Methods We characterized the macrophage and renal responses after ischemia-reperfusion injury with contralateral nephrectomy in LysM-Cre;Arg1fl/fl mice and littermate controls and used in vitro coculture of macrophages and tubular cells to determine how macrophage-expressed arginase-1 promotes kidney repair. Results After ischemia-reperfusion injury with contralateral nephrectomy, Arg1 -expressing macrophages were almost exclusively located in the outer stripe of the medulla adjacent to injured S3 tubule segments containing luminal debris or casts. Macrophage Arg1 expression was reduced by more than 90% in injured LysM-Cre;Arg1fl/fl mice, resulting in decreased mouse survival, decreased renal tubular cell proliferation and decreased renal repair compared with littermate controls. In vitro studies demonstrate that tubular cells exposed apically to dead cell debris secrete high levels of GM-CSF and induce reparative macrophage activation, with those macrophages in turn secreting Arg1 -dependent factor(s) that directly stimulate tubular cell proliferation. Conclusions GM-CSF–induced, proreparative macrophages express arginase-1, which is required for the S3 tubular cell proliferative response that promotes renal repair after ischemia-reperfusion injury.
Battery-Powered Electrocautery and Curettage vs Electrodesiccation and Curettage for the Treatment of Nonmelanoma Skin Cancer
Authors: Kevin K. Veverka, Erik J. Stratman
Journal: JAMA Dermatology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Kidney Biopsy Features Most Predictive of Clinical Outcomes in the Spectrum of Minimal Change Disease and Focal Segmental Glomerulosclerosis
Authors: Jarcy Zee, Qian Liu, Abigail R. Smith, Jeffrey B. Hodgin, Avi Rosenberg, Brenda W. Gillespie, Lawrence B. Holzman, Laura Barisoni, Laura H. Mariani
Journal: Journal of the American Society of Nephrology (2022)

Significance Statement The classification of podocytopathies, including minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS), has historically been based on limited glomerular features. This study used supervised machine learning methods to identify the most important clinical and histopathologic predictors of disease progression, complete proteinuria remission, and treatment response in MCD/FSGS. The top predictors included conventional and novel glomerular and tubulointerstitial features. Biopsy reporting for podocytopathies should be standardized by including these prognostic morphologic features to inform risk stratification. Background Heterogeneity in disease course and treatment response among patients with MCD/FSGS necessitates a granular evaluation of kidney tissue features. This study aimed to identify histologic and ultrastructural descriptors of structural changes most predictive of clinical outcomes in the Nephrotic Syndrome Study Network (NEPTUNE). Methods Forty-eight histologic (37 glomerular, 9 tubulointerstitial, 2 vascular) and 20 ultrastructural descriptors were quantified by applying the NEPTUNE Digital Pathology Scoring System to NEPTUNE kidney biopsies. Outcomes included time from biopsy to disease progression, first complete remission of proteinuria, and treatment response. Relative importance of pathology and clinical predictors was obtained from random forest models, and predictive discrimination was assessed. Results Among 224 participants (34% Black, 24% Hispanic), model performance was excellent, with predictive discrimination of 0.9 for disease progression, 0.85 for complete remission, and 0.81 for treatment response. The most predictive descriptors of outcomes included both conventional— e.g. , global sclerosis or segmental sclerosis and interstitial fibrosis/tubular atrophy—and novel features, including adhesion, interstitial foam cells, deflation, periglomerular fibrosis, mononuclear white blood cells, endothelial cell abnormalities, microvillous transformation, and acute tubular injury. Conclusions The most predictive descriptors of clinical outcomes among MCD/FSGS patients reflected structural changes in multiple renal compartments. Reporting these descriptors should be standardized to guide prognostication of proteinuric glomerular diseases.
Increased activity of the metalloproteinase PAPP-A promotes diabetes-induced glomerular hypertrophy
Authors: Malene R. Jepsen, Jakob A. Østergaard, Cheryl A. Conover, Lise Wogensen, Henrik Birn, Søren P. Krag, Robert A. Fenton, Claus Oxvig
Journal: Metabolism (2022)

BackgroundDiabetic nephropathy (DN) is a serious complication of diabetes and a common cause of end stage renal failure. Insulin-like growth factor (IGF)-signaling has been implicated in DN, but is mechanistically poorly understood. Here, we assessed the activity of the metalloproteinase PAPP-A, an activator of IGF activity, and its possible interaction with the endogenous PAPP-A inhibitors stanniocalcin (STC)-1 and -2 in the mammalian kidney under normal and hyperglycemic conditions.Methods and resultsImmunohistochemistry demonstrated that PAPP-A, its proteolytic substrate IGF binding protein-4, STC1 and STC2 are present in the human kidney. Endogenous inhibited complexes of PAPP-A (PAPP-A:STC1 and PAPP-A:STC2) were demonstrated in media conditioned by human mesangial cells (HMCs), suggesting that PAPP-A activity is regulated by the STCs in kidney tissue. A method for the selective detection of active PAPP-A in tissue was developed and a significant increase in glomerular active PAPP-A in human diabetic kidney relative to normal was observed. In DN patients, the estimated glomerular filtration rate correlated with PAPP-A activity. In diabetic mice, glomerular growth was reduced when PAPP-A activity was antagonized by adeno-associated virus-mediated overexpression of STC2.ConclusionWe propose that PAPP-A activity in renal tissue is precisely balanced by STC1 and STC2. An imbalance in this equilibrium causing increased PAPP-A enzymatic activity potentially contributes to the development of DN, and thus, therapeutic targeting of PAPP-A activity may represent a novel strategy for its treatment.
<i>Notes from the Field:</i> Trends in Gabapentin Detection and Involvement in Drug Overdose Deaths — 23 States and the District of Columbia, 2019–2020
Authors: Christine L. Mattson, Farnaz Chowdhury, Thomas P. Gilson
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Gabapentin is an anticonvulsant medication, which is also approved by the Food and Drug Administration to treat postherpetic neuralgia, a painful complication of shingles, which results from reactivation of the varicella zoster virus.* ,† Gabapentin is commonly used off-label to treat neuropathic pain (1).Gabapentin prescribing has steadily increased in recent years, and in 2019, 69 million gabapentin prescriptions were dispensed in the United States, making it the seventh most commonly prescribed medication nationally.§ Although gabapentin is generally considered safe and is infrequently associated with overdose on its own, when used with other central nervous system depressants such as opioids, there is risk for respiratory depression, potentially resulting in death (2).¶ Gabapentin can be used to potentiate illicit opioids; data indicate gabapentin exposures associated with intentional abuse, misuse, or unknown exposures reported to U.S. poison centers increased by 104% from 2013 to 2017 (3).However, less is known about the drug's role in fatal overdoses (4).To assess quarterly trends in gabapentin-involved overdose deaths of unintentional or undetermined intent during 2019-2020, CDC analyzed data from the State Unintentional Drug Overdose Reporting System (SUDORS) in 23 states and the District of Columbia.**SUDORS requires jurisdictions to abstract data from death certificates and medical examiner or coroner reports, including postmortem toxicology results, * https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020235s064_020882s047_021129s046lbl.pdf † https://effectivehealthcare.ahrq.gov/products/nonopioid-chronic-pain/research§ https://www.iqvia.com/insights/the-iqvia-institute/reports/medicinespending-and-affordability-in-the-us¶ https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-aboutserious-breathing-problems-seizure-and-nerve-pain